Sam Northeast hit an unbeaten century as the South clinched the new North-South series with a 47-run victory at the Dubai International Cricket Stadium.
The Kent Spitfires captain made an unbeaten 118, and shared the match-winning partnership of 170 with Liam Dawson, as the South piled up 346 for six from their 50 overs.
Dawid Malan added 78 to the unbeaten century he scored in the opening game on Thursday, as the South wrapped up the three-game series with a match to spare.
Ben Duckett gave the North a flying start, racing to a 32-ball half-century and sharing a third-wicket stand of 74 with Liam Livingstone.
But after Toby Roland-Jones had Livingstone well caught by Steven Finn off a top-edged hook, Dawson claimed the key wicket of Duckett for 64.
The Hampshire all-rounder went on to finish with two for 46 from his second tidy spell of the series.
But Dawson's figures were slightly dented by Tim Bresnan, who thumped a typically defiant 74 from 66 balls to reduce the North's margin of defeat.
The South will now be aiming for a 3-0 whitewash when the series concludes in Abu Dhabi on Tuesday.